Lack of decay of HIV-1 in gut-associated lymphoid tissue reservoirs in maximally suppressed individuals.

Although peripheral blood mononuclear cells (PBMCs) and lymph nodes represent a principal reservoir, the contribution of gut-associated lymphoid tissue (GALT) has not been evaluated. In 15 HIV-1-infected subjects with maximal suppression of HIV replication by highly active antiretroviral therapy, we quantified HIV-1 DNA and RNA in mucosal biopsy specimens, PBMCs, and plasma with ultrasensitive assays. We also calculated compartmental burdens of HIV-1 DNA-positive cells and characterized the temporal decay of these reservoirs in a period of 1 year (with projections to >50 years). HIV-1 RNA was detected in 20% of the subjects' mucosal biopsy specimens and in 80% of the PBMC samples. Mucosal HIV-1 DNA was detected in 80% of the subjects and in 100% of the PBMC samples. Calculated numbers of lymphoid cells containing "potentially replication-competent" HIV-1 DNA showed that the PBMC compartment contained approximately 70,000 such cells, and GALT contained approximately 160,000 cells. Rates of decay slopes for all 15 subjects in both compartments were not statistically significantly different when compared with each other or with zero slope. Our data indicate that GALT is a quantitatively important reservoir of potentially replicative cells containing HIV-1 DNA, harboring at least as many or more of such cells as the PBMC compartment. In well-suppressed patients on highly active antiretroviral therapy, the GALT compartment showed no clear pattern of HIV-1 decay, similar to that in the PBMCs.

Increased HIV-1 mucosal replication is associated with generalized mucosal cytokine activation.

The purpose of this study was to characterize intestinal mucosal cytokine profiles in subjects with HIV-1 infection and their relation to mucosal viral load (MVL). Intestinal mucosal cytokine mRNA (interleukin [IL]-2, interferon [IFN]-gamma, IL-12, IL-10, IL-1beta, tumor necrosis factor [TNF]-alpha, IL-6, and regulated upon activation, normal T-cell expressed and secreted [RANTES]) and HIV-1 RNA were quantified using real-time polymerase chain reaction (PCR). On the basis of MVL quantification, the HIV-1-infected subjects were divided into 3 groups: undetectable MVL (<50 copies/microg of tissue total RNA), low MVL (>50 but <5000 copies/microg of tissue total RNA), and high MVL (>5000 copies/microg of tissue total RNA). Compared with the control group, significant reductions in RANTES, IL-2, and IFNgamma expression were seen in the undetectable MVL group (P < 0.005). IL-6 was significantly increased in all the HIV groups (P < 0.005), and RANTES, IL-10, and IFNgamma were increased in the high MVL group (P < 0.005). Subjects with high MVL have generalized immune activation with increases in T helper (Th)1, Th2, and proinflammatory cytokines, whereas subjects with undetectable MVL have reduced expression of multiple cytokines. The pathologic basis for these observations is unclear but may relate to the success or failure of antiretroviral therapy in controlling mucosal viral replication.